Anti-Tumor Activity of Cdk2/9 Inhibitor Fadraciclib in an In Vivo Model of Temozolomide Refractory Neuroblastoma.
In a temozolomide-resistant Th-MYCN neuroblastoma mouse model and derived allografts, molecular profiling identified CDK2-pathway deregulation, and fadraciclib treatment produced significant tumor responses and an overall-survival benefit.
Open original publication →What the AI sees
In a temozolomide-resistant Th-MYCN neuroblastoma mouse model and derived allografts, molecular profiling identified CDK2-pathway deregulation, and fadraciclib treatment produced significant tumor responses and an overall-survival benefit.
Research significance
The supplied preclinical evidence supports activity of the CDK2/9 inhibitor fadraciclib in temozolomide-resistant neuroblastoma; it is reasonable, but not yet clinically demonstrated, to hypothesize that CDK2/9 inhibition could overcome or exploit resistance-associated dependencies in relapsed neuroblastoma and improve responses to temozolomide-based therapy.
Source abstract
Advances in preclinical models that recapitulate chemorefractory and relapsed disease are needed to better predict the efficacy of an expanding and promising armamentarium of drug candidates being tested in early-phase pediatric clinical trials. Here, we used longitudinal magnetic resonance imaging to design an individualized, dose-escalating treatment regimen that induces evolution of neuroblastoma in the Th-MYCN genetically-engineered mouse model, concomitant with the acquisition of resistance to temozolomide, a standard chemotherapy used in treatment of refractory, relapsed neuroblastoma patients within European early-phase clinical trials. MRI longitudinally identified the development of intra-tumoral heterogeneity. Molecular profiling of expanding, treatment-refractory regions identified prominent up-regulation of the noradrenergic core regulatory signature and deregulation of the CDK2 pathway. Treatment with the CDK2/9 inhibitor fadraciclib led to significant response and an overall survival benefit in temozolomide-resistant Th-MYCN tumors and allografts generated from these resistant tumours. These findings demonstrate the utility of genetically-engineered mouse models as platforms to dissect the evolution of chemoresistance in neuroblastoma and they provide a mechanistic rationale to support the evaluation of fadraciclib in ongoing paediatric phase I studies of chemotherapy combined with temozolomide in relapsed, treatment refractory neuroblastoma patients.